Our studies include the relationships of biological function to the three-dimensional geometrical and electronic structures of enzymes and their complexes, and of smaller molecules. A recent major accomplishment, the structure to 2.5A resolution of the complex of the allosteric enzyme aspartate transcarbamylase with the potent inhibitor N-phosphonacetyl-L-aspartate, has revealed the active site, and the large conformational changes associated with the transition from the less active (T) form to the more active (R) form. With the use of the now-known diffraction phases, it is planned to relate the effects on three dimensional structure of (a) site specific mutagenesis, (b) chemical modification, (c) natural mutations, and (d) reconstituted hybrids of various catalytic and regulatory protein components. These structural data will be compared with the effects on activity and regulation in order to establish an atomic basis for allosteric behavior. X-ray diffraction studies are being carried out on new complexes of inhibitors and (at low temperatures) substrates with carboxypeptidase A, and on leucine aminopeptidase and a cytochrome P450 (a 17 hydroxylase). Theoretical molecular orbital studies of enzyme mechanisms and X-ray diffraction studies of structures of smaller biologically active molecules are also being made. These studies will illuminate aspects of mechanisms and help to account for the efficient catalytic powers of enzymes.